Autism. Autistic spectrum disorders (ASDs) are severe, chronic, pervasive disorders arising in early childhood. ASDs are characterized by deficits in all aspects of social interaction and reciprocity, pragmatic communication deficits and language delays, and an assortment of behavioral problems such as restricted interests, sensory sensitivities, and repetitive and stereotypic behaviors. The early onset of autism and its familial patterns of origin support a biological basis of origin. At the same time, evidence of a rapid increase in ASD incidence over the past several decades, the complex and highly varied genetic profiles of individuals with ASDs and the repeated demonstration that genetically-identical individuals may or may not develop ASD show that environmental factors also contribute importantly to the early neurological distortions that contribute to its onset.
The predominant scientific views of ASD origin focus on the severe deficits in “theory of mind” contributing to related impairments in “social cognition,” impairments in the development of normal language and related cognitive abilities, delayed and distorted development of executive and social control abilities, or on some form of more general “weak central coherence” impacting most or all brain systems at many or all brain processing levels.
Any theory on the cause of autism must account for the severe deficits in social cognition (SC) that are an invariable part of the disorder. The term “social cognition” refers to mental operations underlying social interactions including the: a) perception, processing and interpretation of information related to them, b) ability to perceive the intentions and dispositions of others; and c) generation and control of responses to those intentions. The scientific literature identifies at least five distinct SC domains: (1) emotion perception: the correct perception of facial and vocal expressions of the emotions in others; (2) social perception: the ability to judge social cues and infer social interactions from contextual information and nonverbal communicative gestures; (3) self-referential style: the explanations that people generate regarding the causes of positive and negative events in their lives (e.g., personalizing bias, “jumping to conclusions”, etc.); (4) theory of mind (ToM): the ability to attribute mental states to others, to make inferences about others' intentions, and to understand that others have mental states that differ from one's own, including false beliefs, hints, intentions, irony, sarcasm, etc.; and (5) empathy: the capability to share and understand other's emotions and feelings.
Recent studies in humans and primates have mapped brain areas related to these different dimensions of social cognition. For example, a distributed network of areas has been shown to be involved in the perception and interpretation of social information, with specific areas argued to sub-serve specific SC functions. The lateral fusiform gyrus, superior temporal sulcus and amygdala are activated by facial and emotion perception tasks. The medial frontal, medial prefrontal and orbitofrontal areas are engaged in ToM-related actions. The ventromedial prefrontal cortex is activated in tasks in which social knowledge guides behavior. The orbitofrontal cortex regulates the values that bias and shape self-referential style in social responding. And the anterior and middle cingulate cortex, the supplementary motor area and the anterior insula are engaged by empathic tasks.
Social cognition deficits characterize individuals with ASD. Impairments in SC associated with impairments in communication are signature deficits of ASD. A level of social functioning necessarily underlies personally and societally satisfactory social and general functionality. Signs of social dysfunction in ASD children are evident within the first 6-12 months of life, emerging earlier than do the hypersensitivities and the restricted and repetitive behaviors that are so strongly associated with ASD. These core deficits in social cognition are strong, persistent, cross-modal, and degrade all SC operations. They underlie the social difficulties that are so diagnostic of autistic spectrum disorders.
It should be noted that for children and adults with high-functioning autism (HFA) and Asperger Syndrome (AS), invariably-present social cognition impairments can be substantially or completely distinct from general cognitive abilities. For many of these individuals, “high functioning” in cognitive terms simply does not equate with “high functioning” in social terms. Because of this distinction in the penetration of different expressions of ASD, SC deficits have been argued to be more primal than ASD origins. This discrepancy between cognitive and social skills clearly affects the ability of adults with HFA and AS to secure employment and live independently, and contributes greatly to their predictably poorer quality of life—even while they may have an acceptable or even high level of cognitive ability and control.
Over the past decades, numerous studies have documented severe deficits of individuals with ASD in virtually every aspect of SC tested. ASD individuals have a poor ability to recognize or distinguish between facial emotions. They are impaired in understanding and interpreting prosodic elements of speech that convey emotion or social meaning. Children with ASDs do not appropriately pair gestures with vocalizations and facial expressions that mark different emotional states. Both adults and children are impaired in both their appreciation and their production of emotional expressions.
Children with ASD have severe problems with processing facial stimuli. They are less likely to attend to faces, are impaired in face discrimination, and have difficulty recognizing familiar faces. Opposite to normal individuals, ASD patients spend twice as much time looking at the mouth region than at the eyes, which convey more information about complex emotions.
Severe problems in social cue perception, empathy, affect regulation, self-monitoring and gaze perception have been documented in ASD individuals. Impairments in “theory of mind” (ToM) have been richly catalogued. Subjects with ASDs have particular difficulty judging emotions and mental states expressed by the faces, voices or gestures of others.
Abnormal brain areas subserving SC contribute to the origins and expressions of ASDs. According to one theory, an early developmental failure involving the amygdala has a cascading influence on the development of cortical areas that mediate social perception in the visual domain, specifically impacting the “face area” in the fusiform cortex in the ventral temporal lobe. Indeed, recent imaging studies have documented abnormal activation patterns in a distributed SC system in the brains of individuals with ASD that supports this general perspective. SC deficits are invariably paralleled by amygdala hypo-activation or dysfunction.
Correlational studies also link these patterns to the striking deficits in social perception and in early-stage processing abnormalities of facial expressions. Similarly, ASD deficits are expressed by abnormal functionality in the superior temporal sulcus and medial prefrontal cortex. Hypo-activation of the fusiform face area (FFA) has been recorded in several fMRI and PET investigations, along with abnormal structural changes in the right FFA in brains of males with ASD.
A general conclusion from this emerging body of literature is that the severe SC problems characterizing ASD individuals represent at least one of the most elemental expressions—and possibly the primary neurobehavioral problem—at the heart of these disorders.
Current interventions applied to remediate social cognition deficits in ASD have not proven to be satisfactorily effective. Several reports have documented limited positive outcomes achieved with group-based interventions. Clinicians have outlined suggestions and provided workbooks and guidelines for training HFAs and more severe ASD and PDD-NOS groups in SC. Despite relatively sparse and modest documentation of benefits, these methods have been widely applied in clinical and special education school environments. Some individualized therapies designed to improve social functioning have also been studied, again demonstrating positive but modest improvements in SC achieved through very extensive one-on-one therapy.
In general, approaches to SC training are idiosyncratic, fragmented, and grossly incomplete. Few interventions are based on any theoretical understanding of the neurological processes or systems that underlie SC deficits in ASD. For example, almost all treatment approaches rely exclusively on a top-down, direct instructional approach, with no targeting of core neuronal deficits underlying social impairments. Most interventions target one or a few aspects of SC. No strategy developed up to this time applies multi-faceted training to establish more effective social abilities at every SC system level. Moreover, while many interventions drive improvements on trained abilities, they have failed to result in any significant generalization to everyday situations. Group-based or individualized interventions also require trained, experienced personnel, impose geographical barriers for program delivery, and by their nature limit the number of individuals that can participate in or benefit from any given intervention.
ASDs and related Pervasive Developmental Disorders (PPDs) degrade the lives and prospects of about every 60th child brought into our world. Most affected individuals require a high level of ongoing support. Because of their hypersensitivities, their deficits in language and non-verbal expression and their often-severe limitations in social control, rehabilitation, education and home and school life can be very challenging for parents, therapists and teachers. Given their special demands, the support of these individuals is exceptionally costly. Special education services have to be achieved in small groups or one-on-one, and because many individuals have to be continually monitored into—and not infrequently through—adulthood. There is a pressing need for more effective treatment modalities.
Social Cognition. Apart from sufferers of ASD, a subpopulation of normal humans is socially undeveloped in ways that negatively impact their entire lives. For example, social cognition deficits are a near-universal aspect of normal aging, and are especially impactful in pathological aging. Special and more profound social cognition deficits also limit the lives and personal success of 1) other children and adults with a history of pervasive developmental disability; 2) patients with schizophrenia, where there is a severe degradation of social cognition and control; 3) patients with other psychiatric disorders including bipolar disorder, depression, obsessive-compulsive disorder, hoarding disorders, and anxiety disorders—among many others; and 4) individuals with a great variety of social conduct disorders including psychopathic disorders, and oppositional-defiant disorders—among many others.
The standard of care for social skills interventions includes group-based or individual therapies that are widely applied in clinical and special education school environments. Using an instructional approach, children are didactically taught—using educational, top-down instructional strategies dependent on executive function abilities—to practice social skills. But these abilities are commonly very impaired in socially impaired individuals.
While some of these practical and scientific approaches to SC training have shown good compliance and usually improve directly trained skills in the research environment, current available programs and interventions fall short. Indeed, most well-controlled studies of available SC training approaches have documented modest or no generalization to everyday social behaviors or control.
Positive improvements in social cognition are a crucial facet of establishing or restoring the health and life-quality of millions of children and adults with these (and other related social-impairment) conditions.
Attention Deficit and Hyperactivity Disorder (ADHD). More than 9% of American children (more than 13% of American boys) now formally acquire the “ADHD” (Attention Deficit and Hyperactivity Disorder) label before their 18th birthday. Approximately half of those children (now nearly 3 million in the US) are prescribed stimulant drugs to address their problem.
ADHD puts a child at risk for limited success, and for failure at and dropout from school. There is a strong co-morbidity with disruptive behavioral disorder, specific language impairments and reading impairments, and cognitive, executive control and social control impairments. Children with ADHD have less regular and often-disruptive sleep patterns. They are at much higher risk for the development of addictions. They are more prone to having a driving accident. They are many times more likely to commit a felony in later life. On the statistical average, they have negative impacts for the social health and well-being of their parents and families. While there are many outstanding exceptions, an ADHD diagnosis foretells a poorer quality of life and a less productive, less stable and more socially perilous adolescence and young adulthood.
While the expressions of ADHD are richly variable in the 5.4 million children identified with this disorder in the US, impaired kids differentially express two broad classes of attentional deficits. ADHD children are 1) inattentive, often disengaged, and unresponsive; and 2) impulsive, easily distracted and frequently disruptive.
Scientists have identified different aspects of behavior and distorted neurology that contribute to the complexly differently nuanced expressions of ADHD. These include deficits in 1) baseline levels of awareness (deficits in ‘arousal’ or ‘brightness’); 2) decoding (correctly recognizing and interpreting what the child has just seen or heard); 3) brain speed and associated fluency; 4) working memory and delayed recall; 5) control of focused attention with high spatial and temporal selectivity, and with flexibly controlled intensity of focus; 6) sustained attention on-task over the epochs of time required for task completion, 7) control of attention in multi-tasking (for example, when a child must bring different aspects of a compound task flexibly into the foreground, or carry it back to the background), and 8) appropriately suppressing responses triggered by normally-distracting or disrupting (normally non-attended) stimuli. All of these aspects of attention impairment and control are manifested neurologically, primarily expressed by abnormal activities in neurological processes localized to well-described frontal, parietal, middle and inferior temporal and ventral occipital cortical areas.
The current standard of care is to prescribe stimulant drugs like Ritalin or Adderall, which result in the mild, broad, temporally non-selective amplification of forebrain neurological activities. From a neurological perspective, for a brain that is limited in its decoding operations, this is akin to turning up the volume on your radio so that you can more easily understand the message, when the real problem is that you are not accurately tuned into the station. Moreover, broad, indiscriminate drug-induced amplification increases the power of important neurological events AND the power of activities representing noises and distractors.
Because stimulant drugs like Ritalin or Adderall—like cocaine or other endogeneously-administered opioids—result in an increase in the circulating levels of neurotransmitters controlling overall levels of ‘arousal’—they also (like cocaine or methamphetamine) result in a down-regulation of the brain's native production of those neurotransmitters. Interestingly, when these drugs are initially administered in ADHD children, relatively strong impacts on the child's level of engagement largely attributable to this broad, non-specific increase in the level of ‘arousal’ are recorded. However, carefully controlled trials supported by the National Institutes of Health have shown that the ameliorative impacts of ADHD-targeted drugs slowly fade; in time, there is no measurable distinction between the control of attention in drug-treated vs drug-virgin or behaviorally-treated children. Moreover, in time, ADHD-related profiles recorded in children who stopped taking their medicine cannot be distinguished from those same indices in children who have faithfully continued taking stimulant medicines.
Given these outcomes, it is perhaps not surprising that about 50% of children are non-adherent drug users at 1 year, or that in the large government-supported MTA study, less than 40% of initially-medicated children were taking any medicine 7 years later. At the same time, doctors routinely prescribe ADHD-targeted stimulants for use throughout childhood, the application of these drugs in young adults is rapidly growing, and there is growing pressure to regard ADHD as a continuous, lifelong chemical-stimulant-treatable malady.
In contrast to drug treatment, behavioral approaches apply parent or therapist-implemented coaching or small-group training strategies designed to improve the behavioral and social control of the ADHD child. While the delivery of this form of help has been repeatedly shown to be useful (especially importantly when the child has a comorbid conduct disorder), cost of delivery of this help is high, the majority of children have no access to effective treatments in these forms, improvements in cognitive and social control abilities are sketchy, and the neurological distortions that are the actual bases of inattention and distraction remain unaddressed by this training.
Computer-based training designed to recover key abilities have been shown to positively impact ADHD, with the strongest impacts expressed for inattention/low-arousal and impulsivity indications in the disorder. The ‘Fast ForWord’ programs developed by a team led by the BPI Director Michael Merzenich have been shown to substantially correct decoding, brain speed, working memory, impulse control and focused-attention deficit aspects of ADHD. However, the distractability and disruptive deficits expressed in the ADHD profiles of trained children were not corrected by the use of these tools. Furthermore, Fast ForWord training is limited to the aural speech domain, resulting in improvements that did not generalize to significant attention control in visual operations.
A Swedish group led by Dr. Torkel Klingberg constructed ‘CogMed’ computerized training tools targeting visual working memory, showing that this training has a strong impact in this specific trained skill domain. While specific training in impulse control did drive positive improvements in the trained skill domain, the benefits did not generalize to control of impulsivity or other cognitive control abilities.
A number of other computer-delivered training program suites have focused on attention training. All express some or all of the same limitations that apply for the Fast ForWord and CogMed programs, i.e., 1) are limited to one neurological modality (e.g., to vision or aural language); 2) do not directly address key underlying distortions in the brain's “arousal” system, in brain speed, or in other elementary processing abilities that support memory and impulse control abilities; 3) sketchily address social control and executive control aspects of ADHD; and 4) almost universally, do not address problems associated with the second great factor underlying ADHD, the inherent high distractibility (high sensitivity to disrupting internal or external distractors) that is at the heart of the sustained-attention and hyperactivity dimensions of ADHD.
Mindfulness training (meditation) has been shown to have positive impacts on ADHD expressions in limited studies. But meta-analyses documenting results from the wider literature are less optimistic. Moreover, this potentially useful adjunctive training strategy does not address many of the fundamental neurological distortions that are the bases of the complex expressions of ADHD.
Finally, many ADHD children are treated by biofeedback strategies designed to alter neurological responses that are believed to manifest or contribute to the disorder. Many positive reports of biofeedback- or magnetic stimulation-induced impacts in the literature are counter-balanced by a handful of gold-standard studies that show limited or no benefits.
In sum, no currently available treatment effectively corrects the complex panoply of behavioral and neurological deficits that are expressed in ADHD. The predominant treatment modes can have initial positive impacts, but treatment impacts aren't sustained, the fundamental neurological problems that underlie ADHD remain uncorrected, and in the end, the expression of the child's problems show no long-term differences between treated or untreated or treatment-withdrawn children.
Depression and Mood and Anxiety Disorders. Major depressive disorder (MDD) is a common, recurrent and disabling condition marked by significant impairments in social and occupational functioning. MDD is the third leading cause of global disease burden, with annual costs exceeding $50 billion in the U.S. workplace alone. The lifetime prevalence of depression is 17% in the U.S., where more than 1.5 million years/annum are lost to MDD-related disability. Suicide is the 10th leading cause of death in the U.S., and two-thirds of all suicides are committed by individuals with MDD. Despite the availability of a variety of medical approaches, up to 50% of patients do not respond to psychological or pharmacological treatments. In the U.S., standard care results in remission (complete recovery) in only one of three MDD patients. Nearly 40% of patients who do recover relapse back into MDD within two years. This occurs in part because many patients voluntarily abandon antidepressant treatment, partly due to what for them are intolerable side effects. In light of these staggering statistics, it is clear that many unmet needs remain in the treatment and relapse prevention of MDD.
MDD and mood and anxiety disorders (MA) are associated with deficits in attention, executive function, learning and memory. Individuals with MDD or MA are particularly impaired at inhibiting or disengaging attention from negative information, and amplify the significance of personal failure by committing more errors immediately after mistakes. It has been suggested that these deficits play a key role in the emergence and maintenance of negative processing biasing, which has been implicated in the etiology of depression and MA. In addition, broadly generalized deficits in processing speed contribute to these cognitive and social-emotional control abnormalities. Impairments in baseline attention further exacerbate cognitive and social impairments and contribute to the social anxiety and withdrawal that can lead to profound degradation of quality of life.
Behavioral and neuroimaging studies in MDD have revealed dysfunctional cognitive and social control systems, with marked deficits in the dorsolateral prefrontal cortex (DLPFC) and dorsal ACC in the former case, and in the amygdala, rostral anterior cingulate cortex (rACC) and other para-limbic structures in the latter18. Slower information processing is broadly expressed across cognitive and social-control systems, and within the perceptual and cognitive processing machinery that sub-serves them. Deficits in alertness, a key impairment in MDD, have been attributed to dysfunction within a broad network of regions that include the locus coeruleus (LC) in the brainstem as well as medial prefrontal and inferior frontal-parietal cortical areas, predominantly in the right hemisphere. The LC synthesizes norepinephrine, an excitatory neurotransmitter intimately involved in arousal. LC neurons widely innervate and normally amplify responses in the forebrain, with especially strong effects in frontal areas that are dysfunctional in MDD. Importantly, these same areas—most notably the amygdala, inferior frontal-parietal cortex and medial prefrontal regions—project back to the LC, regulating its activity. Metabolically down-regulated cells in the LC in MDD patients are reduced in sizes and numbers, and have greatly dis-elaborated cortical terminal projections. Sizes, metabolism and terminal distributions of LC neurons are all correlated with depression severity, suicide risk, and other life-quality variables.
In spite of a myriad of psychological and pharmacological therapies for MDD, there is still no effective treatment for a large proportion of patients. When treatments do help overcome depressive symptoms, underlying neurobehavioral impairments (e.g., processing speed, cognitive control processes, novelty seeking) commonly remain uncorrected. In addition, reduced cognitive control and abnormal post-error adjustments have been described in individuals with current and past MDD, in patients with elevated dysphoria, and in psychiatrically healthy individuals carrying genetic variants linked to MDD risk, suggesting that these deficits represent core MDD vulnerabilities.
In addition to their limited efficacy for many patients, long-term use of antidepressant medication is expensive, and often results in unwanted side effects. Problems arising from drug withdrawal and justifiable fear of relapse promote long-term—and not infrequently, life-long—drug usage. Psychotherapy (e.g., cognitive behavioral therapy that is usually focused on coping with environmental stressors, cognitive restructuring of negative thoughts, and ‘consciously elevating’ mood) is a more benign treatment approach, but given the prevalence of low arousal states and dysphoria in MDD, compliance can be poor, treatment failure rates again approach 50%, and relapse is common.
From a neuroscience perspective, MDD originates as an experience-driven distortion in the processes of the ‘plastic’ human brain. Psychotherapy treatments have focused on the reduction of the psychological traumas, distresses and anxieties that (among other impacts) result in a dysregulation of the systems that control baseline levels of alertness and attention as well as cognitive control and social-emotional processes. Pharmacological treatments increase the circulating levels of modulatory neurotransmitters that are dysregulated as a consequence of neurological distortions in the arousal and cognitive control centers in the forebrain attention network. Neither treatment fully addresses the complex, emergent neurological distortions characteristic of MDD. Even when effective, standard treatments require long-term if not life-long medication or behavioral therapy, and leave the patient with a strong risk of illness recurrence.
Traumatic Brain Injury. About one in five Americans incur one or more ‘mild’ or ‘moderate’ traumatic brain injuries that shall bring them to a hospital emergency room or clinic sometime over the course of their lifetimes. About 1.7 million such injuries, sine qua non with diffuse brain damage, are reported in the U.S. each year. Studies in animal models and in human populations have shown that the neurological impacts of such injuries are cumulative. For example, a head injury that results in a concussion increases the probability that an equivalent second blow to the head will induce another concussion; that second concussion can be induced by a substantially weaker subsequent blow; and repeated concussive injuries generate progressively more severe and more enduring behavioral and neurological expressions of broadly distributed brain damage.
Some populations are at especially high risk for more-severe or repeated head injuries. Approximately 300,000 of the 1.6 million men and women who have served in the armed forces in Iraq and Afghanistan, have incurred a TBI; more than 90% of those injuries are categorized as falling within the ‘mild’ to ‘moderate’ part of the clinical spectrum. In the very hazardous physical environment of the Iraq/Afghanistan, about one in three of these individuals have suffered repeated TBIs.
Remarkably, up to about 80% of TBI soldiers and veterans were subjected to blast injuries, which have a high incidence for generating diffuse brain damage. The pressure waves generated by nearby explosions can generate vacuolization (thousands of tiny foci of damage) and induce diffuse damage of axons in both fiber tracks and ‘gray matter’ throughout the brain. The neurological consequences of such injuries can be long enduring, and can affect almost every aspect of brain function. Many tens of thousands of Iraq/Afghanistan veterans have neurobehavioral deficits attributable to blast injuries that can be expected to degrade their ability to function and thrive in the military, and in their post-military civilian lives.
In the US civilian population, about half a million individuals incur a medically-reported concussive injury arising from sports or leisure activities each year. While the single most common cause of a concussive TBI in the civilian population is a bicycling accident, a more serious medical challenge arises from contact sports like boxing, hockey, American football, lacrosse or soccer, in which there is a high probability of repeated brain injury. Studies using sensors mounted in the helmets of American football players, for example, document about a thousand potentially-brain-damaging blows incurred through a high-school or college career for a typical individual American football player. It should be noted that there has been a long-standing presumption that head blows that do not result in concussion present little risk for an athlete, but many animal studies and more-current human studies challenge this proposition. Clear evidence of physical brain damage can be recorded in non-concussed collegiate football players through the course of a playing season. There are professional and collegiate players who acquire a head injury-induced form of early senility who had little or no history of concussions during their playing careers. For a professional football player, cumulative brain injuries almost certainly account for their nearly 20-fold increase in their risks for early-onset Alzheimer's disease. Years of added risk portending an earlier onset of senility appear to result from engagement in any contact sports to the level of a professional or collegiate athlete.
Traumatic brain injuries commonly induce other neurological problems that can further degrade cognitive abilities, and the qualities of life of injured individuals. The majority of TBI patients have post-injury sleep disruption, a problem that can be long enduring. Most have recurring headaches that can plague the TBI sufferer long after their injury. Diffuse brain injury generates abnormal, destabilizing brain activities not infrequently expressed as epileptiform ‘sharp spikes’, or less commonly, by emergent frank epilepsy. A TBI sharply increases the risks of onset of major depressive disorder. Repeated head trauma can result in a neurodegenerative condition called ‘chronic traumatic encephalopathy’ that foretells Alzheimers-like pathology emerging at a young age. As noted earlier, the occurrence of a TBI very significantly shortens the predicted time to onset of Alzheimer's Disease itself. Finally, TBIs arising from a traumatic experience—or in individuals like military veterans, law enforcement officers or health care professionals who might be exposed to repeated traumatic events—are often accompanied by post-traumatic stress disorder (PTSD). Given the overlap in the neurological expressions of PTSD and TBI, diffuse brain injury very substantially increases the probability that PTSD will arise in an individual who has experienced, or subsequently experiences disturbing events. Co-morbid PTSD significantly increases the TBI patient's neurological burden and cognitive impairments, and very significantly impedes their passage back to a normal, stable and productive life.
A number of these problems emerge and grow after the TBI incident, indicating that damage sets destructive change processes in motion that can progressively amplify dysfunction. Headaches, neurological instability, depression, chronic traumatic encephalopathy, PTSD and other associated sequelae can all contribute to what can be growing problems for a traumatically brain injured individual.
Diffuse traumatic brain injuries induce immediate, widely distributed damage to axonal connections in the brain, and to both subcortical and cortical “gray matter.” The physical blow or blast appears to result in breakage of the stiff microtubules that transport nutrients, neurotransmitters and other materials in axons, supporting axon and terminal (synapse) vitality. As a result of this and other damage, there is a significant diffuse loss of axonal projections and synapses. The disruption of axonal transmission and the local swelling and degeneration of axons manifest thousands to millions of these “micro-damage” events in the human brains of a typical TBI-affected patient, with the regions of maximum damage roughly associated with the domains of most-significant neurobehavioral losses that result from the trauma. In a healthy, young brain, there can be substantial physical recovery from these losses, in the sense that axonal swelling and dieback can recover after the initial injury. However, losses in connectivity incurred by the TBI degrade local brain connectivity and reduce connectional reliability, and greatly increase intrinsic brain process “noise” (neuron network “chatter”).
Although there is substantial individual variability in this expressed pathology, damage relatively predictively and disproportionately affects certain neuronal systems and processes. For example, changes in blood perfusion patterns, alterations in resting state connectivity, and the documentation of distortions in neurological responses evoked by specific explicit behaviors known to be affected by “mild” or “moderate” TBI record the most prominent physical and functional changes in the subcortical caudate nucleus, thalamus and cerebellar vermis, and in middle and lateral anterior frontal cortex, the superior temporal cortex and the posterior cingulate cortex. At the same time, a large body of evidence has shown that the functionality and sustained connectivity of these specific brain areas are strongly dependent on the integrity of the machinery and the quality of the information at “lower levels” in the complex neurological systems that feed them—indicating that the recovery of the physical integrity and the functionality of these systems represent the real therapeutic targets.
Most civilian and military TBI patients have speed-of-processing deficits. Such deficits, grossly impacting the efficiency of neurological operations in recognition and responding, are associated with that increase in “noise” (“chatter”) in the TBI brain, with weakened inhibitory processes affecting widely distributed brain areas. Again, the microtrauma-induced damage to axonal projection pathways and the reduction of elaboration of connectivity within brain networks is the probable primary source of this increased chatter.
A large proportion of patients have attention deficits expressed by lowered baseline levels of arousal or attention, and by impairments in selective and sustained attention. A heightened susceptibility to disruption of attention by distractors often adds to the TBI patient's difficulties at staying on task in attention- and memory-demanding behaviors. Sleep regulation deficits also stem from this dysregulation of arousal, attention control and distractor control processes associated with TBI.
Many individuals with TBIs have deficits in working memory, memory span, and delayed recall. Deficits are sometimes not evident on standardized testing, but are revealed when the memory task engages divided attention or involves multi-tasking, or is evaluated in more-cognitively-demanding task scenarios.
Working memory contributes importantly to “cognitive control” abilities; deficits in these higher-order cognitive control processes have been repeatedly documented in TBI. Not surprisingly, those deficits in “cognitive control” or “executive control” have been correlated in different studies with both processing speed and working memory deficits. In this domain of cognitive control, individuals with TBI often have special problems in reward discounting and in associated impulse control and aggression that almost certainly contribute to their greater risks for succumbing to substance abuse and other addictive behaviors. These deficits are especially marked in individuals with co-morbid PTSD.
Problems in social cognition and social control can be especially impactful for an individual with TBI because a degradation of social cognition can contribute so importantly to employment success, and to the effective reconnection of the brain-injured individual with their partners, families and communities. About half of individuals with TBIs have difficulties in recognizing and responding appropriately to facial affect or gesture-expressed emotions; a larger proportion have problems in higher-order aspects of social cognition that impact interactive social skills, attachment and empathy.
Childhood Abuse.
Stressed and abused children who endure multiple negative factors in their social environments express altered levels of cortisol and noradrenaline in their bodies and brains. While the cortisol/noradrenaline responses to stress underlie our effective somatic and neurological responses to danger/threat that help assure our survival, unabated stress (cortisol & noradrenaline release) has enduring negative functional and physical impacts on elemental learning processes and on the modulatory control machinery governing learning-induced plasticity in their brains. High circulating levels of noradrenaline and the delayed maturation of inhibitory processes in the brain contribute to a greatly elevated risk of onset of an anxiety syndrome. At the same time, paradoxically, the brain's own production of noradrenaline, dopamine, serotonin and acetylcholine—all key “neuro-modulators”—are down-regulated, which, paradoxically, results in a weakened resilience against the later onset of a depressive disorder.
There are more than two million Americans with a history of abuse in which these contrary neurological effects ultimately cycle from a period of down- to up- to down-regulation of these processes, expressed as an emergent bipolar disorder. Moreover, many stressed and abused children have attention control deficits encompassing problems with both a) inattentiveness and b) ‘hyperactivity’ associated with impulsivity and difficulty in controlling responses to distractors. These changes obviously relate to the down-regulation of intrinsic noradrenaline release and to blunted responses to cortisol release that stem from their strong engagement of the HPA axia in periods of stress or abuse. Furthermore, most distressed and abused children have distortions in reward-weighting processes in their brain that, combined with their cognitive control deficits and impulsive responding, put them at high risk for the later emergence of destructive addictive and compulsive behaviors.
Also, most distressed and abused children have deficits in social cognition that impair social interaction success and weaken their development of attachments and empathy. These deficits, which contribute strongly to a degraded quality-of-life, also foretell a greatly increased probability that societal alienation shall ultimately result in criminal offense and incarceration. They frustrate the chances that a child that has been subjected to ongoing stress or abuse shall have a thriving, social, successful older life
Alzheimer's. Alzheimer's Disease (AD) is a ‘neurodegenerative disease’ marked by the pathological formation of beta-amyloid within neurons and in extracellular tissues, by the formation of amyloid crystals that, with soluble aggregated forms of amyloid, poison and render dysfunctional brain cells in the immediate areas in which they form—and by the formation of microfibrillary ‘tangles’ within nerve cells, which directly destroy their functionality and ultimately result in cell death. The punctate amyloid deposits and the areas with the highest levels of ‘soluble oligomeric assemblies’ of amyloid and associated compounds initially arise within the brain machinery controlling its most complex neurological operations, in what has been called the “default system” of the brain. Many studies have now demonstrated that this machinery controls our most complex, sophisticated and abstract operations in thought, planning, rumination, and mental reconstruction.
More than a decade ago, scientists showed that this highest-level brain machinery becomes de-vascularized in individuals who have AD. More recent studies have shown that a sharp drop in blood perfusion and glucose utilization first evident in these brain areas is recorded in individuals who are at high risk for AD onset. Over this past decade, it has been repeatedly shown that the “default system” becomes less strongly engaged in the normal course of aging. Importantly, the degree of this “functional disconnection” resulting in default system inactivity is directly correlated with the emergence of the pathological markers of AD. That explains the parallel decrease in its blood supply: Blood perfusion in cortical tissues—and their metabolic and immunological integrities—are controlled by levels of activation of brain tissues. These areas are largely shut down—relatively inactive, metabolically down-regulated, and immunologically compromised—in the at-risk or AD individual.
In our own studies, we have shown that “noise” (neuronal “chatter”) grows progressively in the brain as we age. That growing noise results in natural “plastic” changes in the way that the brain represents, by its neural activities, the details of what you see or hear or feel or smell. Because those striking changes ultimately greatly degrade the quality, and sharply reduce the power for engagement, of information that is “fed forward” to the default-system level of our brain operations, the “highest levels” of our great brain systems are the first to be functionally disconnected in age-related decline. The emergence of AD pathology adds to this progressive, highest-level de-activation because it directly adds to an individual's “brain noise,” weakens feedback to lower brain system levels, and thereby further degrades affected brain systems. The AD slowly encroaches on neighboring brain areas. Ultimately, inexorable, growing changes result in the loss of the ability to control even the most elemental of receptive and expressive neurological functions.
What underlies the poisonous production and release of amyloid and amyloid-body formation in the first place? What engenders the destructive proliferation of microtubules in nerve cells? We know that they are both contributed to by compromised immune processes, but how do we explain immune system weakening? We know that pathological markers first arise in inactivated brain regions, but how, exactly, do changes in activity result in that poisoning?
Certainly the reduced blood perfusion attributable to changes in neuronal activity is an almost-certain important contributor. A recovery of more normal perfusion resulting from more normal levels of default system engagement would presumably result in immune system strengthening. Moreover, the increased brain activity expressed through a functional recovery of the default system should result in its parallel metabolic recovery.
We also know that there is a substantial down-regulation of brain-produced noradrenaline in most aged individuals, and that the physical (metabolic; neuronal population; noradrenaline production) status of the primary brain source of noradrenaline, the mid-brain locus coeruleus, is directly correlated with cognitive performance abilities AND with risks of AD onset in elder populations. Noradrenaline is a key regulator of the sub-population of micro-glial cells that scavenge infectious agents and debris in brain tissues. Damage to the neurons supplying noradrenaline results in a rapid increase in amyloid production and release. Increasing circulating levels of noradrenaline in older brains results in a faster clearance of cellular debris following focal lesions AND increases the scavenging of soluble amyloid itself.
The inactivation of the default system in aging results in a dis-elaboration of synaptic connections and ultimately to cell death. Both of these negative changes provide rich sources of prions and other amyloid-attracting brain matter debris. Moreover, the emergent AD pathology leads to more death and destruction, which exacerbates the problems in sustaining functional integrity by impaired immune system machinery.
Finally, changes in synaptic processes related to neuronal activity levels in AD disease models have been argued to lead to a cascade of changes that result in intracellular amyloid accumulation that plausibly sets neuro-pathological processes (intracellular amyloid accumulation and release; tau accumulation; cell death) in motion. These changes arise, again, in forebrain structures that are functionally decoupled.
It should be noted that by this new brain plasticity-based perspective about the origins of AD, it is not a ‘disease’ in the classical sense. To the contrary, AD represents a scenario in which the brain poisons itself because it is unable to sustain its immunological integrity, and because it cannot sustain activity levels necessary to sustain metabolic and physical integrity. Immunological compromise occurs, first of all, because large regions of the aging brain come to be inactive, and because of that inactivity, de-vascularized. That inactivity arises in turn, very naturally, from a slow increase in the ‘noisiness’ of older brains, which degrades the quality and power of the encoded information (neural activity) that engages highest-level brain processes. As those sources of information are degraded in quality and power, their ability to engage our highest brain levels slowly dissipates.
In the frontal cortex in the brain, areas in this now-devascularized and degraded machinery regulate the activity of the locus coeruleus (LC). The LC broadly amplifies activity in the brain whenever we have a novel or unexpected experience, such as a surprise. It is relatively poorly activated due to a more limited exposure to new experiences in most older individuals, but that problem is exacerbated by a weakening of feedback from the frontal cortex that plays a critical role in defining new experiences as novel or unexpected. The slow deterioration of this machinery adds to the immunological compromise of the brain, again expressed with greatest power in the “default system.”
There are five other important aspects of AD that bear implications about how we should think about delaying or preventing its onset in any given individual. First, we now know that the pathology emerges long before functional deterioration results in an AD diagnosis. For example, using markers that allow us to image amyloid plaques and micro-fibrillary tangles in living brains, we now know that more than half of 70 year olds express this AD pathology, at an age at which only 7% have received the AD label. In general, the pathology is in place and growing apace roughly a decade before the destruction reaches the level that results in the formal AD clinical label.
Second, we also now know that there can be a substantial discordance between an individual's functional disabilities and the pathological state of their brain. Some individuals with relatively weakly expressed neuro-degeneration are profoundly impaired, while others with marked pathology retain the cognitive and social-emotional abilities that assure a healthy, independent older life. That implies that even when the pathology is in place and growing, the right kind of brain activities can sustain functional abilities in ways that can assure continuing independence.
Third, studies have long shown that there is a greater susceptibility and predicted earlier age of onset for AD for a small proportion of genetically-identifiable individuals who acquire this devastating conditions in their 40's or 50's or 60's. This subpopulation now has relatively bleak prospects for a healthy older life. Most can look forward to spending many years in continuous care in their later decades. If we had an effective strategy for delaying AD onset, every individual should be in line to undergo this important genetic testing. Now, few do.
Fourth, while AD is often described as a genetic illness, many environmental factors have been shown to add months to years of risk for onset. Almost all of these factors plausibly contribute to an increase in ‘brain noise’—that is, to the ultimate source of AD pathology.
Finally, several drugs have now been shown to reduce amyloid plaques and micro-fibrillary tangles in AD patients by directly blocking plaque formation or by amplifying immune system responses. Alas, that wondrous result has little or no impact on the behavioral expressions of the illness in active AD patients. For strategies designed to break down amyloid plaques, patients actually got worse.
Addiction. Nearly 18 million Americans (8.5%) meet stringent (DSM-IV) medical criteria for alcohol abuse and alcoholism (AAA). Success rates for self-treatment (voluntary withdrawal with maintenance of safe drinking levels) from AAA are low. Well-developed organized treatment programs achieve rates of sustained recovery that range from less than 20% to a high of 60%. Overall, relapse is expected to occur for a substantial majority of alcoholics who have completed a treatment program, with most relapses occurring within the first three months after treatment.
Alcohol has large-scale, progressive dose-related consequences in the brains of alcoholics. Because alcohol alters fundamental biological processes contributing to excitability and communication between brain cells (neurons), it ultimately impacts every aspect of perceptual, cognitive, executive control and action control processing in the brain. Beyond the changes that contribute to craving- and other dependency-related behaviors, those who suffer AAA undergo broadly expressed cognitive losses that degrade an alcoholic's abilities to sustain employment and social success.
On an elementary level, alcohol affects the basic properties of neuronal excitability and communication. Under alcohol's sustained influence, cortical activities are suppressed and cortical networks become less complex. With this deterioration of connectivity, the brain's information processing is slowly degraded. Under the toxic effects of ethanol, the brain undergoes “reverse-plasticity” changes that simplify its operations. The myelin insulation on the brain's ‘wires’ that support rapid and reliable communication in brain networks and between functional areas in brain systems become degraded. As a consequence of these changes, broadly affected brain areas shrink in physical volume.
As these toxic effects progress, the alcoholic's brain struggles to sustain its usual high-fidelity, high-speed operations. The progressively “noisier” machinery of the heavily alcohol-exposed brain is manifest by reduced cognitive performance. Memory and attention control abilities deteriorate. There is a reduced ability to perform long range planning. The AAA individual struggles to resist impulses to gain immediate small rewards, eschewing what would be bigger rewards if those impulses were controlled. Impulsive response weakness in reward-weighted tasks is correlated with indices of AAA in both juvenile and adult populations.
With a continuance of drinking, there is a demonstrable deterioration in reasoning and social- and response-control abilities. In parallel with those changes, the rewarding impacts of heavy alcohol dosing directly distort the machinery that calibrates the values of extrinsic rewards. In effect, alcohol intake causes the release of neurotransmitters that would ordinarily guide behavior toward accomplishing positive, adaptive goals, but instead steers behavior to alcohol-related activities. Among other distortions, the brain comes to be strongly excited by the prediction that alcohol is in the offing. This reflexive craving at the prospect of alcohol, embedded in the brain by its habitually rewarded consumption, is a “failure mode” of our self-organizing plastic brain.
The neurological distortions found in alcoholics are also commonly found in methamphetamine and opioid drug users, and other addicts.
Brain systems are biased in their processing in ways that perpetuate the addiction. Ingesting drugs releases dopamine and is thought to encode motivation to procure the drug irrespective of whether or not consumption is pleasurable. With chronic use, the brain loses dopamine D2 receptors necessary for reading the dopamine signal. As a consequence, the addict must ingest more drugs to achieve the same rewarded state (i.e., tolerance develops). Downstream corticolimbic areas are negatively affected, exhibiting tonic hypoactivity to natural (non-drug) rewards and transient hyperactivity to the drug(s) of abuse. Brain regions shrink, and connectivity weakens, contributing to deficits in executive control, goal-directed behaviors, and long-term memory. Decreased amygdala volume correlates with craving, and probability of relapse. Cues associated with drugs that contribute to craving alter orbitofrontal cortex (OFC) by amplifying activities representing those ‘triggers.’ Magnitudes of brain dysfunction are correlated both with the durations of substance abuse and real-world shortcomings. These abnormalities generate maladaptive feed-forward processes that sustain drug use and create the foundation for the cognitive and neuro-behavioral deficits that are symptomatic of addiction. As the addiction progresses, impairments in cognition, attention and cognitive control are supported by degraded deficits in processing speed, representational salience, and working memory.
Schizophrenia.
Schizophrenia is a severe, chronic mental illness that affects more than two million individuals in the U.S. The healthcare burden attributable to schizophrenia is estimated at $62 billion annually, and is expected to grow as many treatment programs fail to successfully re-integrate these individuals into the larger society. These costs are largely incurred by the functional impairments in living, work, and everyday function, which are an essential diagnostic feature of the illness, found in many patients with schizophrenia. These poor functional outcomes are manifested by the high rates of unemployment, poor social and community functioning, reduced capabilities for independent living, and a generally reduced quality of life.
These fundamental deficits in functional ability in schizophrenia are largely attributable to pervasive and enduring impairments in social cognition (SC): the perception, interpretation and processing of social information. Individuals with schizophrenia exhibit deficits in all core domains of SC: emotion perception (the recognition of facial and vocal affect), social cue perception (the ability to detect and comprehend cues in a social context), theory of mind (the mental capacity to infer one's own and others' mental states), attributional style (attribution of causes of events to the self, to others, or to factors in the environment), and empathy (the ability to share, understand and appropriately react to the emotional states of others). Notably, impairments in each of these domains have been shown to have a significant impact on functional outcome in schizophrenia.
These fundamental, multi-domain SC impairments are not only directly linked with poor social functioning (i.e., inadequate social relationships, weak attachments, limited social support), but also underlie most critical factors of daily living in schizophrenia, such as occupational status, community functioning, independent living skills, relapse rate, and quality of life. Moreover, the degree of SC impairment is a stronger predictor of the level of everyday functional ability than are cognitive abilities or the severity of positive symptoms. This makes SC an important treatment target in schizophrenia. As the ultimate goal of therapeutic interventions is to improve life outcomes for patients, recovery of these individuals to the broader society is dependent upon the recovery of their SC abilities. The fact that SC deficits persist throughout the course of the illness, are seen in prodromal patients, and are even present in unaffected relatives of patients, further stresses their central role in schizophrenia and fuels the need for an effective, scalable treatment for SC deficits.
These severe and broad-ranging SC deficits in schizophrenia are rooted in anatomical and functional abnormalities within a complex brain network collectively termed “the social brain.” Specifically, significant anatomical and/or functional abnormalities have been localized to the superior temporal sulcus (STS), anterior insula, amygdala, medial prefrontal cortex (mPFC), and to the cingulate cortex, all are known to be critically involved in perception and processing of social information. Further, abnormally-weak connectivity between functionally-related, cortical and subcortical areas, as well as between sensory cortices and higher-level areas has led to a growing characterization of schizophrenia as an “information processing disorder”. Collectively, these abnormalities further imply that effective treatments for schizophrenia should target SC dysfunction from their neurological core, by aiming to improve the speed of processing and accuracy of stimulus representation of social information in the core brain areas which underlie SC.
Despite the importance of SC as a primary source of impairment, frustrating successful treatment and real-world recovery of patients with schizophrenia, there are currently no well-accepted or even broadly administered methods for improving SC function in this large patient group. Further, SC deficits are resistant to pharmacological treatments including second-generation antipsychotic medications that are effective for controlling positive symptom levels. Perhaps more surprisingly, new and demonstrably effective interventions for treating cognitive deficits in schizophrenia have been shown to have only limited impacts on social functioning—perhaps because SC deficits are associated with impaired function of neural networks that are largely distinct from, and parallel those subserving more general cognition. The delivery of an effective, practical, affordable, and scalable solution for this specific need is therefore of the highest clinical significance.
Several experimental, therapist-delivered approaches targeting social skills or SC have been developed over the last decade. These interventions are offered in relatively few clinics nationwide and are usually administered by trained professionals individually or in small groups over the course of several months. The therapist-administered options usually focus on emotion management and social skills building, and require multiple in-person visits to the clinic in the course of a few months. Recently, some computer-aided interventions have been created, but they are limited in scope (mainly target a single SC domain in isolation, facial affect recognition), have undergone only initial testing in schizophrenia, and are not used, to the best of our knowledge, in any clinical treatment programs.
While recent studies have shown the promise of social skills and SC interventions, to date, no single treatment has been widely adopted or is currently seeking FDA clearance for patient reimbursement, and there is no standard of care for SC treatment in schizophrenia. Although the various interventions differ from one another in dosage, mode of administration, and targeted deficit(s), the majority have the following traits in common. First, they use a ‘top-down’ training strategy, utilizing explicit instructions and coaching strategies in which participants are taught how to work around their deficits. These strategies rely heavily on executive control, declarative memory, and strategic thinking abilities, all of which are substantially impaired in schizophrenia, effectively limiting the potential benefits of this approach. Second, they employ limited stimulus variation, in which only a small number of social stimuli can be modeled in individual or group-administered sessions. Individuals are exposed to a limited set of socially relevant stimuli and scenarios, which may be reducing the potential for generalization beyond the context of therapy. Third, they use a ‘one size fits all’ approach, whereby group interventions are administered in an identical format to all participants, without regard to individual differences in level of social functioning across the five major SC domains. Finally, they are not scalable or cost-effective, because they require highly-trained personnel and necessitate frequent visits to the clinic. The relatively large costs associated with their delivery therefore limit the scalability of these forms of treatment to the larger schizophrenia population.
Notably, the goal of SC interventions is to improve functional outcomes by improving social abilities. Rigorous studies that would elucidate the degree of recovery in SC function that must be achieved to support true real-world abilities are therefore highly required. Nonetheless, outcome studies involving the interventions described above have had important limitations, making it difficult to determine which therapeutic approach is actually most effective. First, sample sizes are often small, fail to rigorously account for heterogeneity in the schizophrenia population, and provide little basis for determining predispositions for training gains in the population. Second, the lack of adequate controls that are matched for intensity and experimenter contact have made it difficult to conclusively attribute performance gains to outcomes. Third, the use of only one or two, often non-standardized, SC or functional outcome measures limits our understanding to the true nature of intervention, and its potential for generalization outside the training setting.
In recent years, special emphasis has been given to the need for early intervention in schizophrenia. It is now acknowledged that the early phase of psychotic illness is crucial in terms of the emergence of a range of cognitive deficits that have prognostic implications, and that early intervention can potentially prevent further worsening of symptoms and improve functioning. An important target for early intervention is the domain of social cognition, the mental operations that underlie understanding, interpretation and perception of social information. Severe social cognition deficits, often comparable to those seen in chronic patients, have been repeatedly documented in early-phase schizophrenia. These deficits span the domains of affect perception, social cue perception, including gaze perception, theory of mind, and attributional style.
Importantly, social cognition deficits have been strongly associated with poor functional outcome in schizophrenia. Specifically, affect recognition and social perception have been each linked with community functioning, social problem solving and social skills. ToM, as well as affect perception and social perception, have been found to mediate the relationship between neurocognition and functional outcome. Surprisingly, however, only a few studies to date have examined the direct effects of social cognition training in young adult or early psychosis patients, and none have evaluated a computerized intervention. Studies testing the effects of Cognitive Enhancement Therapy, a computer-based cognitive training with group-based social skills training and of SCIT, a social cognitive group intervention in first episode patients report promising effects on neurocognitive, social cognitive and functional outcome measures. However, these encouraging outcomes are limited by the practicality of applying these treatments in many clinical settings, given long treatment durations, the need for a trained clinician team, and the necessity of organizing patient groups for program delivery.